Abstract Number: OC 16.1
Meeting: ISTH 2021 Congress
Background: Hemophilia A (HA) is a rare bleeding disorder caused by absence or dysfunction of FVIII protein. Little is known about the origin of spontaneous bleedings in severe HA patients and standard therapies are ineffective in preventing recurrent joint and intracranial bleedings. To date the impairment of vessel stability in HA patients is not clearly explored and a correlation between FVIII and endothelial functionality has never been explained.
Aims: To elucidate the potential role of FVIII in endothelial stability and investigate significant differences in HA and healthy endothelial cells (ECs).
Methods: iPSCs-derived ECs, both from HA patients and healthy donors, were used as ECs models. HA-ECs were transduced with a lentiviral vector (LV) carrying the B- deleted form of FVIII under the control of an endothelial promoter (LV-VEC.FVIII). RNA-Seq and proteomic analyses were performed to evaluate differences in healthy, HA ECs and LV-VEC.FVIII-transduced HA ECs. To investigate ECs impairment in vitro and in vivo assays were performed.
Results: RNA-Seq and proteomic analyses, revealed different gene expression and protein profiles in HA vs healthy ECs; the impaired phenotype was partially attenuated in LV-VEC.FVIII transduced HA ECs. Several genes were down regulated in HA ECs compared to healthy ECs, suggesting an impairment in HA ECs stability. These data were validated in vitro, showing a weakening in tubulogenesis, migration potential and permeability of HA ECs vs healthy ECs. The transduction with LV-VEC.FVIII improved ECs functionality, suggesting the potential involvement of FVIII. These data were confirmed also in a mouse model of HA, showing altered permeability and tubulogenesis potential of HA vessels compared to wild type mice.
Conclusions: These preliminary results if confirmed in primary ECs can provide new insights into unexplored roles for FVIII, offering new therapeutic gene and cell therapy strategies in the management of HA patients.
To cite this abstract in AMA style:Olgasi C, Cucci A, Borsotti C, Walker G, Molineris I, Anselmi F, Assanelli S, Sgromo C, Oliviero S, Follenzi A. From Coagulation to Angiogenesis: Extra-coagulative Role of FVIII [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/from-coagulation-to-angiogenesis-extra-coagulative-role-of-fviii/. Accessed May 16, 2022.
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